[Changes in Attitudes to Medical Care among Pharmacy Pharmacists before and after the COVID-19 Pandemic: A Questionnaire Survey].

The coronavirus disease 2019 (COVID-19) pandemic has had a major negative effect on the number of patients visiting pharmacies in Japan. The decrease in pharmacy visits during the pandemic compared with the pre-pandemic period may have increased the likelihood of adverse health outcomes; thus, it is important that pharmacy pharmacists take measures to prevent health disadvantages. In this study, we distributed a questionnaire survey to 104 pharmacy pharmacists (mainly in Kagoshima and Kumamoto Prefectures), and investigated changes in the extent of implementation and perceptions of measures considered necessary to protect patients' health between the pre-pandemic and pandemic period. The results showed that the proportions of respondents "sharing patient information between primary care doctors and pharmacy pharmacists" and conducting "follow-up after prescribing medications mainly via telephone" increased between the pre-pandemic period and September 2022. The perceived necessity of the above two measures, as well as "online medication instructions" and "a prescription refill system," increased during the same period. However, the proportion of respondents who perceived "0410 correspondence," which was introduced during the pandemic, as a necessity did not change. Moreover, many pharmacists indicated that, at their own discretion, they continued to correspond with patients in relation to the above, and to respond to specific requests during normal daily practice. Our results could help community-based pharmacists tackle serious public health problems, such as COVID-19.

Evaluation for Blood Concentration and Efficacy/Safety of Continuous Administration of Thiamylal in Children.

BACKGROUND: Thiamylal exerts excellent sedative effects. However, it is not routinely used because of its serious adverse effects. This study aimed to clarify the target blood concentration range and infusion rate of thiamylal in children by measuring its blood concentration and evaluating its relationship with efficacy and adverse effects. METHODS: This study was approved by the Ethics Committee of Japanese Red Cross Kumamoto Hospital. The authors included 10 children aged between 1 and 7 years who had received continuous intravenous (IV) infusion of thiamylal for the management of refractory status epilepticus, excluding those who met the exclusion criteria. After a 2 mg/kg bolus injection of thiamylal, continuous IV infusion was initiated at a rate of 2-3 mg/kg/h. Thiamylal concentration in the blood was measured using high-performance liquid chromatography. The State Behavioral Scale and the frequency of bolus injections were used to evaluate efficacy. Blood pressure and heart rate were measured to evaluate adverse effects. Statistical analyses of the time to awakening and the factors affecting it were also conducted. RESULTS: The State Behavioral Scale score during thiamylal administration was -2 or lower in all cases, suggesting that the depth of sedation was sufficient. The frequency of bolus injections decreased in a blood concentration-dependent manner, suggesting that the frequency tended to decrease, especially at thiamylal blood concentrations of 20 mcg/mL or higher. An increase of the infusion rate to 3 mg/kg/h was recommended, because the blood concentration may not reach 20 mcg/mL at an infusion rate of 2 mg/kg/h. There was also a case in which a rapid increase in blood concentration accompanied by a decrease in blood pressure and heart rate was observed when the infusion rate was increased to 4 mg/kg/h. Furthermore, the time to awakening after the end of administration correlated with the highest blood concentration during administration; therefore, delayed awakening was noted when using a high dose of thiamylal. CONCLUSIONS: The target blood concentration of thiamylal in children should be 20-30 mcg/mL, and the infusion rate should be based on 3 mg/kg/h.

Questionnaire survey on pharmacists' roles among non- and health care professionals in medium-sized cities in Japan.

Although the scope of pharmacists' work has expanded in Japan, people's perception of this is unclear. To contribute to medical care together with non- and health care professionals, clarifying the perceptions of these groups is important to best utilize pharmacist professionals. We conducted a cross-sectional questionnaire survey among non-health care professionals (n = 487) and nurses (n = 151), medical doctors (n = 133), and pharmacists (n = 204) regarding the work of pharmacists. The questionnaire comprised 56 items in four categories associated with the roles of pharmacists. For each questionnaire item, we performed logistic regression analysis to compare pharmacists' opinions with those of other professionals and non-health care professionals. Opinions were similar between pharmacists and nurses or medical doctors regarding "collecting patient information" and "providing drug information to patients." However, there were differences in perceptions regarding "medical collaboration" (nurses; 8/23 items, physicians; 11/23 items) and "community medicine" (nurses; 9/15 items, physicians; 11/15 items), and pharmacists themselves perceived greater roles related to health care collaboration and community health care. Perceptions of non-health care professionals were poorer than those of pharmacists in all categories (47/56 items). These results suggest that pharmacists must actively communicate to help others understand their specialty and build trusting relationships to improve patient care.

Knowledge and Awareness of Human Papillomavirus Vaccination and Cervical Cancer among Men and Women in Japan: A Questionnaire Survey.

BACKGROUND: In many advanced countries other than Japan, the incidence and mortality rates of cervical cancer, which is mainly caused by the human papillomavirus (HPV) infection, are decreasing probably due to the high rate of HPV vaccination and cervical cancer screening. In Japan, these rates are on the rise owing to the stagnation of vaccination and low screening rate. To improve these situations, active promotion of HPV vaccination and screening is required. As a preliminary stage, we investigated perceptions regarding cervical cancer and HPV vaccines among Japanese men and women and examined the difference in perceptions by sex. METHODS: This was a prospective cross-sectional questionnaire survey targeting Sojo University students and working adults. University students were targeted before learning about cervical cancer. Working adults were recruited on the basis of information from the Health Promotion of Health and Welfare Department of Kumamoto Prefectural Government in Japan and from companies via student organizations promoting cancer prevention. We surveyed respondents' knowledge and awareness about HPV vaccination and cervical cancer and performed logistic regression analysis to compare the results between men and women. RESULT: A total of 557 completed questionnaires (205 men and 352 women) were analyzed. Women had high levels of knowledge and awareness about HPV vaccination and cervical cancer compared with men. However, 70% of women surveyed had never been screened for cervical cancer. CONCLUSION: A total of 557 completed questionnaires (205 men and 352 women) were analyzed. Women had high levels of knowledge and awareness about HPV vaccination and cervical cancer compared with men. However, among surveyed women, the degree of knowledge and awareness was lower than that among women in other countries with established HPV vaccination programs. Furthermore, 70% of women surveyed had never been screened for cervical cancer.

Gut microbiota of Parkinson's disease in an appendectomy cohort: a preliminary study.

In patients with Parkinson's disease (PD), α-synuclein pathology is thought to spread to the brain via the dorsal motor nucleus of the vagus nerve. The link between the gut microbiome and PD has been explored in various studies. The appendix might play an important role in immunity by maintaining the microbiota as a reservoir. In recent times, appendectomy has been linked to a lower risk of PD, possibly owing to the role of the appendix in altering the gut microbiome. We aimed to elucidate whether the gut microbiota affects PD development in the appendectomy cohort. We analyzed the fecal microbial composition in patients with PD and healthy controls with and without a history of appendectomy. The abundance of microbes from the family Enterobacteriaceae was higher in feces samples from patients with Parkinson's disease compared to that in samples collected from healthy controls. Furthermore, there was a significant phylogenetic difference between patients with PD and healthy controls who had undergone appendectomy. There was a significant phylogenetic difference between patients with PD and HCs who had undergone APP. These results suggest the correlation between gut microbiota and PD in patients who have undergone APP.

An Alternative Application of Natural Language Processing to Express a Characteristic Feature of Diseases in Japanese Medical Records.

BACKGROUND: Owing to the linguistic situation, Japanese natural language processing (NLP) requires morphological analyses for word segmentation using dictionary techniques. OBJECTIVE: We aimed to clarify whether it can be substituted with an open-end discovery-based NLP (OD-NLP), which does not use any dictionary techniques. METHODS: Clinical texts at the first medical visit were collected for comparison of OD-NLP with word dictionary-based-NLP (WD-NLP). Topics were generated in each document using a topic model, which later corresponded to the respective diseases determined in International Statistical Classification of Diseases and Related Health Problems 10 revision. The prediction accuracy and expressivity of each disease were examined in equivalent number of entities/words after filtration with either term frequency and inverse document frequency (TF-IDF) or dominance value (DMV). RESULTS: In documents from 10,520 observed patients, 169,913 entities and 44,758 words were segmented using OD-NLP and WD-NLP, simultaneously. Without filtering, accuracy and recall levels were low, and there was no difference in the harmonic mean of the F-measure between NLPs. However, physicians reported OD-NLP contained more meaningful words than WD-NLP. When datasets were created in an equivalent number of entities/words with TF-IDF, F-measure in OD-NLP was higher than WD-NLP at lower thresholds. When the threshold increased, the number of datasets created decreased, resulting in increased values of F-measure, although the differences disappeared. Two datasets near the maximum threshold showing differences in F-measure were examined whether their topics were associated with diseases. The results showed that more diseases were found in OD-NLP at lower thresholds, indicating that the topics described characteristics of diseases. The superiority remained as much as that of TF-IDF when filtration was changed to DMV. CONCLUSION: The current findings prefer the use of OD-NLP to express characteristics of diseases from Japanese clinical texts and may help in the construction of document summaries and retrieval in clinical settings.

Association of Clostridium butyricum Therapy Using the Live Bacterial Product CBM588 with the Survival of Patients with Lung Cancer Receiving Chemoimmunotherapy Combinations.

The gut microbiota has emerged as a key regulator of immune checkpoint inhibitor (ICI) efficacy. Therapeutic approaches aimed at manipulating the microbiota through targeted reconstitution to enhance cancer treatment outcomes have garnered considerable attention. A single live microbial biotherapeutic bacterium, Clostridium butyricum MIYAIRI 588 strain (CBM588), has been shown to enhance the effects of ICI monotherapy in patients with advanced lung cancer. However, whether CBM588 affects the outcomes of chemoimmunotherapy combinations in lung cancer remains unknown. We hypothesized that CBM588 augments the effect of chemoimmunotherapy combinations and restores diminished effectiveness in patients with non-small cell lung cancer (NSCLC) receiving dysbiosis-inducing drugs. To validate this hypothesis, we retrospectively analyzed 106 patients with stage IV or recurrent metastatic NSCLC consecutively treated with chemoimmunotherapy combinations. A survival analysis was performed employing univariate and multivariate Cox proportional hazard models with inverse probability of treatment weighting (IPTW) using propensity scores. Forty-five percent of patients received Clostridium butyricum therapy. CBM588 significantly extended overall survival in patients with NSCLC receiving chemoimmunotherapy. The favorable impact of CBM588 on the efficacy of chemoimmunotherapy combinations varied based on tumor-programmed cell death ligand 1 (PD-L1) expression. The survival benefit of CBM588 in the PD-L1 <1% cohort was higher than that in the PD-L1 1-49% and PD-L1 ≥ 50% cohorts. Furthermore, CBM588 was associated with improved overall survival in patients receiving proton pump inhibitors and/or antibiotics. CBM588-induced manipulation of the commensal microbiota holds the potential to enhance the efficacy of chemoimmunotherapy combinations, warranting further exploration of the synergy between CBM588 and immunotherapy.

A novel murine model of autoimmune dysautonomia by α3 nicotinic acetylcholine receptor immunization.

We aimed to establish a novel murine model of autoimmune autonomic ganglionopathy (AAG), which represents autoimmune dysautonomia, associated with MHC class II to understand its pathomechanism and the pathogenicity of nicotinic acetylcholine receptor (nAChR) antibodies. The amino acid sequence of the mouse nAChRα3 protein was analyzed using an epitope prediction tool to predict the possible MHC class II binding mouse nAChRα3 peptides. We focused on two nAChRα3 peptides in the extracellular region, and experimental AAG (EAAG) was induced by immunization of C57BL/6 mice with these two different peptides. EAAG mice were examined both physiologically and histologically. Mice with EAAG generated nAChRα3 antibodies and exhibited autonomic dysfunction, including reduced heart rate, excessive fluctuations in systolic blood pressure, and intestinal transit slowing. Additionally, we observed skin lesions, such as alopecia and skin ulcers, in immunized mice. Neuronal cell density in the sympathetic cervical ganglia in immunized mice was significantly lower than that in control mice at the light microscopic level. We interpreted that active immunization of mice with nAChRα3 peptides causes autonomic dysfunction similar to human AAG induced by an antibody-mediated mechanism. We suggested a mechanism by which different HLA class II molecules might preferentially affect the nAChR-specific immune response, thus controlling diversification of the autoantibody response. Our novel murine model mimics AAG in humans and provides a useful tool to investigate its pathomechanism.

Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer.

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I-IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer.

Novel nitric oxide donor, nitrated phenylbutyrate, induces cell death of human pancreatic cancer cells and suppresses tumor growth of cancer xenografts.

Pancreatic cancer has a low response rate to chemotherapy due to the low drug transferability caused by the low blood flow around the tumor. In the present study, focusing on nitric oxide (NO) for its vasodilatory and antitumor effects, a novel NO donor, a nitrated form of phenylbutyrate (NPB) was synthesized and the antitumor effect on human pancreatic cancer cells (AsPC1 and BxPC3) and xenografts was examined. Using Annexin V, NPB was confirmed to induce cell death against AsPC1 and BxPC3 in a time­ and concentration­dependent manner. In NPB­exposed cells, DAF­FM DA (a probe to detect intracellular NO) derived fluorescence was observed. Release of nitrite and nitrate from NPB in aqueous solution was very gradual until even 72 h after dissolution. Phenylbutyrate (PB) and hydroxy PB in which the nitro group of NPB was replaced with a hydroxyl group did not have the cell death­inducing effect as observed in NPB. These results suggest that the effect of NPB was dependent on NO release form NPB. Apoptosis inhibitor, Z­VAD FMK, had no effect on the cell death­inducing effect of NPB, and NPB did not show significant activation of caspase­3/7. In addition, NPB significantly decreased cellular ATP levels, suggesting that necrosis is involved in the effect of NPB. NPB also accumulated cells specifically at the S phase of the cell cycle. A single dose of NPB (10 mg/kg) into mice with established BxPC3 xenografts significantly suppressed tumor growth for at least 7 weeks without apparent toxicity. The findings of the present study indicate that NPB has potential as a novel therapeutic agent for NO­based therapy of pancreatic cancer.

Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events.

Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell-derived interleukin (IL)-21 upregulated B-cell-homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti-PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management.

Clostridium butyricum therapy restores the decreased efficacy of immune checkpoint blockade in lung cancer patients receiving proton pump inhibitors.

Oral microbiota is associated with human diseases including cancer. Emerging evidence suggests that proton pump inhibitors (PPIs), which allow the oral microbiome to translocate into the gut, negatively influence the efficacy of immune checkpoint blockade (ICB) in cancer patients. However, currently there is no effective treatment that restores the decreased efficacy. To address this issue, we retrospectively evaluated 118 advanced or recurrent non-small cell lung cancer (NSCLC) patients treated with ICB and analyzed 80 fecal samples of patients with lung cancer by 16S metagenomic sequencing. Clostridium butyricum therapy using C. butyricum MIYAIRI 588 (CBM588), a live biotherapeutic bacterial strain, was shown to improve the ICB efficacy in lung cancer. Thus, we investigated how CBM588 affects the efficacy of ICB and the gut microbiota of lung cancer patients undergoing PPI treatment. We found that PPI treatment significantly decreased the efficacy of ICB in NSCLC patients, however, CBM588 significantly restored the diminished efficacy of ICB and improved survival. In addition, CBM588 prolonged overall survival in patients receiving PPIs and antibiotics together. The fecal analysis revealed that PPI users had higher abundance of harmful oral-related pathobionts and lower abundance of beneficial gut bacteria for immunotherapy. In contrast, patients who received CBM588 had lesser relative abundance of potentially harmful oral-related bacteria in the gut. Our research suggests that manipulating commensal microbiota by CBM588 may improve the therapeutic efficacy of ICB in cancer patients receiving PPIs, highlighting the potential of oral-related microbiota in the gut as a new therapeutic target for cancer immunotherapy.

Predictors of hematoma as a complication in pediatric kidney biopsies.

BACKGROUND: Kidney biopsies are crucial in the diagnosis of kidney diseases but they carry the risk of various complications, most commonly hematoma. Here we tried to identify the predictors of hematomas as a complication of kidney biopsies and we constructed an algorithm to stratify the risk. METHODS: The present report retrospectively reviewed 118 pediatric percutaneous kidney biopsies of native kidneys in 102 children (59 females) with the median age of 9 years (range: 1-19 years) at Kumamoto University Hospital between August 2008 and October 2019. We defined hematoma size using the hematoma index: the short axis of the hematoma/major axis of the kidney on ultrasonography. The inclusion criteria for a hematoma as a complication of a kidney biopsy were hematoma index ≥0.1 and the presence of concomitant, post-kidney biopsy fever or flank pain. RESULTS: Eight patients presented with a hematoma as a complication. All had hematoma index ≥0.1 and age ≥6 years. On univariate logistic analysis, these patients had a larger hemoglobin (Hgb) decrease on post-biopsy day 1, which was unrelated to a Hgb decrease 2 h after the biopsy, than the patients with no hematoma. All eight patients with a hematoma presented with a fever or flank pain on post-biopsy days 5 to 7, underscoring the need to observe patients with decreased Hgb carefully for about 1 week after a biopsy. CONCLUSION: Predictors of hematoma as a complication in children after a kidney biopsy were hematoma index ≥0.1, age >6 years, and Hgb decrease ≥15% on post-biopsy day 1.

Characteristics of anal canal cancer in Japan.

Anal canal cancer (ACC) has been reported to be an uncommon cancer in Japan, as in the USA, Europe, and Australia. This retrospective multi-institutional study was conducted to clarify the characteristics of ACC in Japan. First, the histological ACC type cases treated between 1991 and 2015 were collected. A detailed analysis of the characteristics of anal canal squamous cell carcinoma (SCC) cases was then conducted. The results of the histological types revealed that of the 1781 ACC cases, 435 cases (24.4%) including seven cases of adenosquamous cell carcinomas were SCC and 1260 cases (70.7%) were adenocarcinoma. However, the most common histological type reported in the USA, Europe, and Australia is SCC. Most ACC cases are adenocarcinomas and there is a low incidence of SCC in Japan which is different from the above-mentioned countries. Moreover, we reclassified T4 into the following two groups based on tumor size: T4a (tumor diameter of 5 cm or less) and T4b (tumor diameter of more than 5 cm). The results of the TNM classification of SCC revealed that the hazard ratio (HR) to T1 of T2, T3, T4a, and T4b was 2.45, 2.28, 2.89, and 4.97, respectively. As T4b cases had a worse prognosis than T4a cases, we propose that T4 for anal canal SCC in Japan be subclassified into T4a and T4b.

Clinical impact of cerebral infarction in patients with non-small cell lung cancer.

BACKGROUND: Lung cancer patients have a high risk of cerebral infarction, but the clinical significance of cerebral infarction in advanced non-small cell lung cancer (NSCLC) remains unclear. This study aimed to comprehensively investigate the incidence, prognostic impact, and risk factors of cerebral infarction in patients with NSCLC. METHODS: We retrospectively examined 710 consecutive patients with advanced or post-operative recurrent NSCLC treated between January 2010 and July 2020 at Kumamoto University Hospital. Cerebral infarction was diagnosed according to the detection of high-intensity lesions on diffusion-weighted magnetic resonance imaging regardless of the presence of neurological symptoms during the entire course from 3 months before NSCLC diagnosis. The prognostic impact and risk factors of cerebral infarction were evaluated based on propensity score matching (PSM) and multivariate logistic regression analysis. RESULTS: Cerebral infarction occurred in 36 patients (5%). Of them, 21 (58%) and 15 (42%) patients developed asymptomatic and symptomatic cerebral infarction, respectively. PSM analysis for survival showed that cerebral infarction was an independent prognostic factor (hazards ratio: 2.45, 95% confidence interval (CI): 1.24-4.85, P = 0.010). On multivariate logistic regression analysis, D-dimer (odds ratio [OR]: 1.09, 95% CI 1.05-1.14, P < 0.001) and C-reactive protein (OR: 1.10, 95% CI 1.01-1.19, P = 0.023) levels were independent risk factors. CONCLUSION: Cerebral infarction occurred in 5% of NSCLC patients, and asymptomatic cerebral infarction was more frequent. Cerebral infarction was a negative prognostic factor and was associated with hyper-coagulation and inflammation. The high frequency of asymptomatic cerebral infarction and its risk in NSCLC patients with these conditions should be recognized.

The Nitrated Form of Nateglinide Induces Apoptosis in Human Pancreatic Cancer Cells Through a Caspase-dependent Mechanism.

BACKGROUND/AIM: Nitric oxide (NO) has antitumor activity against various solid tumor cell types in addition to its vasodilatory effect. In the current study, we investigated the effect and mechanism of the synthetic nitrated form (NO2-NAT) of nateglinide, a hypoglycemic agent, on the induction of cell death in human pancreatic cancer cells. MATERIALS AND METHODS: NO production was evaluated by measuring nitrite (NO2) and nitrate (NO3) (NOx). Apoptotic cell numbers were determined using annexin V. RESULTS: NO2-NAT released nitrate and nitrite ions immediately upon dissolving in aqueous solution. NO2-NAT caused significant extracellular leakage of lactate dehydrogenase (LDH) in the human pancreatic cancer cell lines AsPC1 and BxPC3, and increased annexin-positive cells in a time- and concentration-dependent manner. NO2-NAT also significantly increased the activity of caspases 3 and 7. Exposure to Z-VAD-FMK, a caspase inhibitor, significantly suppressed NO2-NAT-induced cell death. CONCLUSION: These results indicated that NO2-NAT induces apoptosis in human pancreatic cancer cells and may serve as a new NO-based chemotherapeutic agent for the treatment of pancreatic cancer.

Consistency between patients and families in recognizing cancer chemotherapy side effects: A questionnaire survey.

BACKGROUND: Although the side effects of cancer chemotherapy impair a patient's quality of life, family members' awareness of side effects may relieve patient anxiety and distress. AIM: We investigated whether patients and their families were consistent in recognizing the occurrence and severity of symptomatic side effects of chemotherapy treatment for cancer. METHODS AND RESULTS: This was a prospective observational study. We administered a questionnaire survey to patients and family members to assess the frequency of occurrence (1: never, 2: almost never, 3: sometimes, 4: frequently, 5: almost always, 6: unknown) and the degree of severity (1: mild, 2: moderate, 3: severe, 4: extremely severe, 5: unknown) of physical and psychological symptoms associated with cancer chemotherapy. Weighted Kappa and Cramer coefficients were used to assess consistency between the two groups. We surveyed 20 pairs of patients (5 men, 15 women) and their families (10 men, 10 women); 17 pairs lived together. The median age was 65.5 years (interquartile [IQR], 58.75, 69.25) for patients and 61.00 years (IQR, 47.25, 71.25) for family members. Of patients, 17 had solid cancer, and three had leukemia. Family members mostly recognized objectively visible symptoms such as hair loss and development of spots and keratinization. However, it was difficult for families to detect invisible subjective symptoms such as weakness, dysesthesia, depressed mood, and unarticulated anxiety. CONCLUSIONS: The results indicated that recognition of invisible subjective symptoms in patients undergoing chemotherapy was difficult even for family members. Therefore, a multidisciplinary approach in which various medical professionals actively communicate with both patients and families is important. Information sharing in collaboration with patients and families could increase understanding of the patient's condition and optimize patient care.

Questionnaire Survey Regarding Troubles and Concerns Related to Clinical Research Based on the Clinical Trial Act for Clinicians and Academics.

The Clinical Trial Act came into force in 2018 in Japan. A questionnaire survey was conducted with personnel at Kumamoto University Hospital engaged in research and development, to explore their perceptions of troubles and concerns about clinical research related to the Clinical Trial Act. We collected 127 comments about troubles and 149 about concerns. Text mining (co-occurrence network and hierarchical cluster analysis) was used to extract the characteristics or tendencies in these comments. The analysis extracted 18 key terms for troubles and 21 for concerns. Most troubles and concerns had to do with concrete examples of clinical research or protocols and biostatistics information. Our results emphasized the importance of clinical research support organizations, and suggested that appropriate workshops and information covering specific situations are necessary to perform clinical research under the new regime.

The Binding of Aripiprazole to Plasma Proteins in Chronic Renal Failure Patients.

The binding of drugs to plasma protein is frequently altered in certain types of renal diseases. We recently reported on the effects of oxidation and uremic toxins on the binding of aripiprazole (ARP) to human serum albumin. In our continuing investigations, we examined the binding of ARP to plasma pooled from patients with chronic renal dysfunction. We examined the issue of the molecular basis for which factors affect the changes in drug binding that accompany renal failure. The study was based on the statistical relationships between ARP albumin binding and biochemical parameters such as the concentrations of oxidized albumin and uremic toxins. The binding of ARP to plasma from chronic renal patients was significantly lower than healthy volunteers. A rational relationship between the ARP binding rate and the concentration of toxins, including indoxyl sulphate (IS) and p-cresyl sulphate (PCS), was found, particularly for IS. Moreover, multiple regression analyses that involved taking other parameters such as PCS or oxidized albumin ratio to IS into account supports the above hypothesis. In conclusion, the limited data reported in this present study indicates that monitoring IS in the blood is a very important determinant in the dosage plan for the administration of site II drugs such as ARP, if the efficacy of the drug in renal disease is to be considered.